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Selective Fluorination Strategies

Abstract

There is a great interest in the synthesis of fluorinated aromatic and heterocyclic compounds, which have a range of applications in the pharmaceutical industry. Many common routes to these compounds, however, are low yielding and or/expensive. This thesis is concerned with novel methods for the synthesis of fluoro-aromatics and fluoro-pyrazoles using conventional fluorinating agents, such as Selectfluor™, as well as using elemental fluorine and the flow reactor technology developed in Durham.

Firstly, elemental fluorine was used to fluorinate a range of aromatics containing electron-donating substituents, using both batch and flow methods. These methods often afforded the desired compound but with little selectivity and low conversion from the starting materials. Following on from this, ipso fluoro-deboronation techniques using Selectfluor™, were employed to improve the selectivity and yields of the reaction and, in many cases, the desired mono-fluorinated arylfluoride could be accessed in good yield. A range of aryl boronic acid derivatives were explored as the substrate and the results showed that trifluoroborate salts were the most useful substrate. The ipso fluoro-deboronation of heterocyclic boronic acid derivatives was also investigated and showed some promising results.

The synthesis of 4-fluoropyrazoles was investigated using three methods. Initially, a two-step process, where the 2-fluoro-1,3-diketone was synthesised and isolated and subsequently reacted with hydrazine, was employed. This allowed a range of 4-fluoropyrazoles to be obtained in high yield and purity. Secondly, a telescoped two-step continuous flow process was employed which did not require isolation of the intermediate 2-fluoro-1,3-diketone. This reaction gave good yields and required less solvent with significantly lower reaction times than the two-step process. Thirdly, C4 mono- and di-fluorination of 3,5-disubstituted pyrazoles was investigated using Selectfluor™ and elemental fluorine. This method gave low conversion from the starting material (50–60 %) but the desired 4-fluoropyrazoles and novel 4,4-difluoropyrazoles could be isolated.